2, 8-diaminodibenzothiophene dioxide and n, n&#39;-derivatives



Patented Nov. 14, 1950 2,8-DIAMINODIBENZOTHIOPHENE DIOXIDE ANDN,N'-DERIVATIV ES Edward Delbert Amstutz, Bethlehem, Pa., assignor toThe Wm. S. Merrell Company, Cincinnati, Ohio, a corporation of DelawareNo Drawing. Application June 24, v194'7, Serial No. 756,795

6 Claims. 1

This invention relates to a new class of chemical compounds including2,8-diaminodibenzothiophene dioxide and certain of its 2,8-N,N'derivatives. This application represents a continuation of myapplication Serial No. 685,787, filed July 23, 1946.

The new compounds possess therapeutic properties and are characterizedby the essential skeletal structure of 2,8diaminodibenzothiophenedioxide as illustrated in its structural formula:

One or more hydrogens of the amino groups in this structure may besubstituted by various modifying groups, including simple alkyl, simpleacyl, and aldehyde addition products with bisulfites or sulfoxylates.The amino or substituted amino groups are positioned para in each ringwith respect to the sulphone group. It should be noted that thesubstituted amino groups in each case are of the type that are readilyconvertible in the animal body to the free amino group, and it isbelieved that this is an essential factor in their physiologicalactivity. One of the amino hydrogens, however, may be advantageouslysubstituted by a nitrogen containing heterocycle, e. g., pyridyl,pyrimidyl, thiazyl.

In general, the new products are crystalline solids of relatively highmelting point. 2.8-diaminodibenzothiophene dioxide is a yellow powderwhich may be further purified to almost colorless crystals, melting inthe region of 329-331 C. and is insoluble in hydrochloric acid solutionsover 10%. The general properties of the parent amino compound may beadvantageously modified by the introduction of relatively non-toxicgroups which are converted in vivo to the free amino. Simple alkyl aminoderivatives of 2,8-diaminodibenzothiophene dioxide of similarcharacteristics may be prepared by substitution of lower alkyl radicalsfor the amino hydrogens, where the alkyl amino group is reducible in theanimal body to the primary amino radical. The basic properties of theamino compounds may be altered by the substitution of acetyl groups. Inthis connection the simpler acyl amino derivatives may be considered theequivalents of the acetamido compounds. Compounds of improved solubilitymay be produced by introducing into the amino groups aldehyde bisulfiteor aldehyde sulfoxylate addition products. Sodium formaldehydesulfoxylate and sodium cinnamaldehyde bisulfite are typical of suchaddition products which, however, include other aldehyde additionproducts of relatively non-toxic nature, including those of sugars, e.g. sodium glucose sulfoxylate.

The introduction of a nitrogen base heterocyclic group into one of theamino groups may also be effected with advantage to produce compounds ofadditionally modified properties. The heterocyclic nucleus is ordinarilylinked at the alpha carbon and the heterocycles available include both5-men1bered and B-memb'ered rings containing one Or more nitrogen atoms,such as pyrimidyl, pyridyl, pyrazolyl, triazolyl, piperazyl, thiazyl,etc. The nitrogen base heterocycle may also contain sulfur as in thecase of the thiazyl radical.

The preparation of the new products will be illustrated in the examplesbelow but the inven tion is not limited thereto. In general, thediaminodibenzothiophene dioxide derivatives are prepared by way of2,8-diaminodibenzothiophene dioxide itself. This compound is preparedfrom dibenzothiophene by halogenation, oxidation and amination. Thediacetamido compound is produced by refluxing with acetic anhydride, andthe tetracetamido compound may be produced by the use of a large excessof acetic anhydride. The aldehyde salt derivatives are produced byreacting the diamino compounds with the appropriate aldehyde bisulfiteor aldehyde sulfoxylate addition product.

The heterocyclic derivatives may be prepared in a step-wise process,using a mixed nitro-halogenodibenzothiophene as a starting material,through oxidation of the sulfide to the dioxide, reduction of the nitrogroup to yield the mixed amino-halogeno compound, condensation of theamino group with an ahalogenoheterocycle, and finally amination of thehalogen group. For example, 2-bromo, 8-nitrodibenzothiophene is oxidizedby a suitable oxidizing agent such as hydrogen peroxide and acetic acidsolution, or chromic anhydride, to the corresponding dioxide. Thiscompound is reduced by means of stannous chloride and hydrogen chloridein acetic acid solution to yield 2-bromo, B-aminodibenzothiophenedioxide. A mixture of this compound with 2-bromopyridine, after slowheating on an oil bath, yields 2-bromo, 8-(N-2-pyridyl)aminodibenzothiophene dioxide, upon cooling, dilution with alcohol,collection, and purification. 2- Amino, 8-(N-2-pyridyl)aminodibenzothiophene dioxide is obtained by heating the mixedbromoheterocyclic amino compound with concentrated aqueous ammonia inthe presence of a trace of copper powder in a heated tube at 170 to 225C. for a period of about hours.

EXAMPLE NO. 1

2,8-diaminodibenzothiophene dioxide This compound is convenientlyprepared in a three-step process as follows:

(a) 2,8-dibromodibenzothiophene Dibenzothiophene (0.054 mole) is treatedwith bromine (0.11 mole) in carbon disulfide. After refluxing on a steambath for 9 days, the carbon disulfide is removed by distillation atabout 60 C. The residue is washed with water and recrystallized fromacetic acid followed by a second recrystallization from aceticanhydride.

The bromination using the same quantity of reactants may be effected inglacial acetic acid in about 8 hours, but the product is difiicult topurify.

(b) 2,8-dibromodibenzothiophene dioxide A suspension of2,8-dibromodibenzothiophene (0.02 mole) in glacial acetic acid (77 ml.)is oxidized with hydrogen peroxide (9.6 ml.) by refluxing for 2 hours.The product is obtained in high yield upon cooling and filtering. Itmelts at 341.0-343.5 C.

(c) 2,8-diaminodibenzothiogohene dioxide A mixture of 21.5 g. of2,8-dibromodibenzothiophene dioxide (0.0585 mole), about 150 ml. ofconcentrated aqueous ammonia, and about 1 g. of copper-bronze are heatedtogether for approximately 8 hours at 200 to 220 C. The crude soliddiamino compound is thus obtained, in. p. 317 to 326 C.Recrystallization from water with the aid of Norit (decolorizingcharcoal) yields almost colorless crystals, in. p. 329 to 331 C.(decomp.)

EXAMPLE NO. 2

Sodium 2,8-diaminodibenzothiophene dioxide bis-formaldehydesulfozrylateA mixture of 2,8-diaminodibenzothiophene dioxide (0.0032 mole) andrecrystallized sodium in which R" is an aldehyde sulfoxylate residue.

2. Sodium 2,8-diaminodibenzothiophene dioxide bis-formaldehydesulfoxylate.

3. 2,8-diaminodibenzothiophene dioxide. 4. Compounds of the formula inwhich R, R1, R2 and R3 are selected from the group consisting ofhydrogen, acetyl, aldehydebisulfite, aldehyde-sulfoxalate andnitrogen-containing 5- and G-membered heterocyclic groups, with theproviso that not more than one of the groups R, R1, R2 and R3 is anN-heterocyclic group.

5. Aldehyde-bisulfite N-substituted aminodibenzothiophene dioxide.

6. Aldehyde-sulfoxylate N-substituted 2,8-diaminodibenzothiophenedioxide.

EDWARD DELBERT AMSTUTZ.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date Dahlen Mar. '7, 1939

4. COMPOUNDS OF THE FORMULA